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Formulations for enhanced bioavailability of zanamivir

A technology of zanamivir and enhancer, which is applied in the field of preparations with enhanced zanamivir bioavailability, and can solve the problems of poor oral bioavailability and the like

Inactive Publication Date: 2014-10-01
ALA WAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, animal studies with the oral form of zanamivir have demonstrated poor oral bioavailability

Method used

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  • Formulations for enhanced bioavailability of zanamivir
  • Formulations for enhanced bioavailability of zanamivir
  • Formulations for enhanced bioavailability of zanamivir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] General Experimental Procedure

[0107] Permeability enhancers such as MCM L8, 61A to 61H Composition, Glycerin, 3-(N,N-Dimethylpalmityl Ammonium) Propane Sulfonate (PPS), Leuclne, Alanine, Gelucire 44 / 14, Tween 20, N-Methylpiperazine, and d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) was mixed separately with zanamivir, vortexed and sonicated. For example, in In the case of MCM L8, the booster is mixed with zanamivir in an amount such that the weight ratio of booster to zanamivir is in the range of about 333:1 to about 1333:1, and when the mixture is subsequently placed in HBSS When diluted to a level where zanamivir was present at a concentration of 15 μg / mL (0.0015%), samples had enhancer concentrations ranging from 0.5% to 2.00%, as shown in the table below. Mixing is performed by sonication (using a bath or probe sonicator), which converts a relatively low viscosity liquid mixture into a stable and non-separating high viscosity or pasty compos...

Embodiment 2

[0126] Method for zanamivir

[0127] Drug solution samples were analyzed by LC-MS / MS using electrospray ionization. The chromatographic system consists of Perkin Elmer series 200 micropumps and autosamplers, equipped with Waters HILIC silica 3 μM, 2.1 x 50 mm column. The mass spectrometer was a PE Sciex API4000 with an electrospray interface in multiple reaction monitoring mode. The specificity of the assay was evaluated and none of the excipients was found to interfere with the analysis of zanamivir. Stock solutions (1 mg / mL zanamivir) were prepared in water. Standards (8 concentrations) were prepared in appropriate matching media (HBSSg or Sprague-Dawley rat plasma containing sodium heparin) and diluted 50-fold with methanol. Experimental samples were treated similarly.

[0128] Prepare an assay stock solution (1 mg / mL zanamivir) in water.

[0129] Standards and samples were prepared in Sprague Dawley rat plasma containing sodium heparin as an anticoagulant. An 8-poi...

Embodiment 3

[0161] Volume of PBS remaining in ID Medication Cannula post-study

[0162] For each intraduodenal dosing group, after administration of 50 μL of dosing solution, a small volume of air bubbles and 125 μL of PBS flush were administered to the dosing cannula. About 30 μL of flush PBS may enter the duodenum after pushing the drug solution and air bubbles into the duodenal lumen. This is presumed to be due to the lower resistance observed from the dosing syringe after the dosing solution and gas bubbles were administered into the duodenal lumen. After the last sampling time point, the abdominal region of the animal was opened and the endoduodenal cannula was removed. The remaining PBS was pushed through the cannula with air and collected in a microcentrifuge tube. Residual PBS droplets adhered to the inner wall of the cannula were observed. After collecting as much PBS as possible from the cannula, the volume of fluid collected from each animal was measured with a pipette, reco...

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Abstract

In accordance with the present invention, there are provided compositions comprising zanamivir and at least one permeability enhancer. The compositions can increase the amount of zanamivir capable of being transported across a cell membrane (such as a Caco-2 cell membrane), and can increase this amount by at least 150% relative to the amount capable of being transported across the cell membrane in the absence of the permeability enhancer. Also provided are oral dosage forms of the compositions, which comprise a therapeutically effective amount of zanamivir and a permeability-enhancing amount of a permeability enhancer. The oral dosage forms can further comprise an enteric- or pH-sensitive coating or layer surrounding the composition. Also provided in accordance with the present invention are methods for treating or preventing influenza infection.

Description

[0001] related application [0002] This application claims priority to US Provisional Patent Application No. 61 / 583,526, filed January 5, 2012, the entire contents of which are incorporated herein by reference. field of invention [0003] The present invention relates to enhancing the permeability and bioavailability of polar active agents such as zanamivir. Background of the invention [0004] Zanamivir is a member of a class of antiviral agents that work by inhibiting viral neuraminidase, an enzyme that is critical for influenza viruses to replicate and infect their hosts. In addition to influenza A and B, avian influenza viruses (H5N1) have also been shown to be susceptible to zanamivir. However, animal studies using the oral form of zanamivir have demonstrated poor oral bioavailability. [0005] Accordingly, there is a need for neuraminidase inhibitor compositions that exhibit enhanced bioavailability and efficacy when administered orally for the treatment or preventi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/351C07D309/14C07D309/12A61P31/16A61P31/00
CPCA61K47/183A61K47/22A61K47/14C07D309/28A61K47/20A61K47/10A61K9/4858A61K31/351A61P31/00A61P31/16
Inventor E·霍尔姆斯M·海勒G·K·奥斯特兰德
Owner ALA WAI PHARMA
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